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Dose-finding Study of BMS-955176 to Treat HIV-1 Infected Treatment-naive Adults

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ClinicalTrials.gov Identifier: NCT02415595
Recruitment Status : Terminated (The trial ended early due to GI intolerability and treatment-emergent resistance.)
First Posted : April 14, 2015
Results First Posted : September 19, 2018
Last Update Posted : September 19, 2018
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare

Brief Summary:
The purpose of this study is to find at least one dose of BMS-955176 that will be safe, effective and tolerable for HIV-1 infected treatment naive adults.

Condition or disease Intervention/treatment Phase
Infection, Human Immunodeficiency Virus Drug: BMS-955176 Drug: EFV Drug: TDF/FTC Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 210 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 2b Randomized, Active-Controlled, Double-Blind Trial to Investigate Safety, Efficacy, and Dose-response of BMS-955176, Given on a Backbone of Tenofovir/Emtricitabine, in Treatment-Naive HIV-1 Infected Adults
Actual Study Start Date : May 12, 2015
Actual Primary Completion Date : May 26, 2016
Actual Study Completion Date : August 21, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Arm 1: BMS-955176 60 mg + TDF/FTC
BMS-955176 at 60 mg active dose per day + BMS-955176 placebo matching 120 mg + efavirenz (EFV) placebo matching 600 mg + tenofovir/emtricitabine (TDF/FTC) 300/200 mg per day, orally
Drug: BMS-955176
HIV Maturation Inhibitor

Drug: TDF/FTC
TDF/FTC

Experimental: Arm 2: BMS-955176 120 mg + TDF/FTC
BMS-955176 placebo matching 60 mg + BMS-955176 at 120mg active dose per day + EFV placebo matching 600mg + TDF/FTC 300/200mg per day, orally
Drug: BMS-955176
HIV Maturation Inhibitor

Drug: TDF/FTC
TDF/FTC

Experimental: Arm 3: BMS-955176 180 mg + TDF/FTC
BMS-955176 at 60mg active dose per day + BMS-955176 at 120mg active dose per day + EFV placebo matching 600mg + TDF/FTC at 300/200mg per day, orally
Drug: BMS-955176
HIV Maturation Inhibitor

Drug: TDF/FTC
TDF/FTC

Active Comparator: Arm 4: EFV + TDF/FTC
BMS-955176 placebo matching 60mg + BMS-955176 placebo matching 120mg + EFV at 600mg per day + TDF/FTC 300/200mg per day
Drug: EFV
EFV

Drug: TDF/FTC
TDF/FTC




Primary Outcome Measures :
  1. Number of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) <40 Copies Per Milliliter (c/mL) at Week 24 Using Food and Drug Administration (FDA) Snapshot Algorithm [ Time Frame: Week 24 ]
    Blood samples were collected for quantitative analysis of plasma HIV-1 RNA. The antiviral efficacy was determined by the number of participants with plasma HIV 1 RNA <40 c/mL at Week 24 using the FDA snapshot algorithm. This used the last on-treatment plasma HIV-1 RNA measurement within an FDA-specified visit window (18 to 30 weeks) to determine response. Analysis was performed on mITT Population, which comprised of randomized participants who received at least 1 dose of BMS-955176/GSK3532795 or EFV.


Secondary Outcome Measures :
  1. Number of Participants With Plasma HIV-1 RNA < 40 c/mL at Weeks 48 and 96 Using FDA Snapshot Algorithm [ Time Frame: Weeks 48 and 96 ]
    Blood samples were collected for quantitative analysis of plasma HIV-1 RNA. The antiviral efficacy was determined by the number of participants with plasma HIV 1 RNA <40 c/mL at Weeks 48 and 96 using the FDA snapshot algorithm. This used the last on-treatment plasma HIV-1 RNA measurement within an FDA-specified visit window to determine response. The analysis was performed using mITT Population (observed), which consisted of participants in the mITT Population excluding participants who had no HIV-1 RNA result data in the assessment visit windows due to discontinuation and who discontinued on or after the date of site notification of study termination by the sponsor (10 October 2016). The data was not collected for Week 96 analysis; as the study was terminated early. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

  2. Number of Participants With Plasma HIV-1 RNA < 200 c/mL at Week 24 Using FDA Snapshot Algorithm [ Time Frame: Week 24 ]
    Blood samples were collected for quantitative analysis of plasma HIV-1 RNA. The antiviral efficacy was determined by the number of participants with plasma HIV-1 RNA <200 c/mL at Week 24 using the FDA snapshot algorithm. This used the last on-treatment plasma HIV-1 RNA measurement within an FDA-specified visit window to determine response.

  3. Number of Participants With Plasma HIV-1 RNA < 200 c/mL at Weeks 48 and 96 [ Time Frame: Weeks 48 and 96 ]
    Blood samples were collected for quantitative analysis of plasma HIV-1 RNA. The antiviral efficacy was determined by the number of participants with plasma HIV-1 RNA <200 c/mL at Weeks 48 and 96 using the FDA snapshot algorithm. This used the last on-treatment plasma HIV-1 RNA measurement within an FDA-specified visit window to determine response. The analysis was performed using mITT Population (observed), which consisted of participants in the mITT Population excluding participants who had no HIV-1 RNA result data in the assessment visit windows due to discontinuation and who discontinued on or after the date of site notification of study termination by the sponsor (10 October 2016). The data was not collected for Week 96 analysis; as the study was terminated early. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

  4. Number of Participants With Newly Emergent Genotypic Resistance Using All On-treatment Isolates [ Time Frame: Week 24 ]
    The emergence of genotypic resistance among samples selected for drug resistance testing were assessed by searching for all reverse transcriptase substitutions and protease inhibitor substitutions listed in the International Acquired Immunodeficiency Syndrome (AIDS) Society-United States of America (IAS-USA) list of HIV-1 drug resistance mutations. The outcome was originally designed to be assessed up to 96 weeks of treatment, but it was analyzed up to Week 24 as the study was terminated early. The emergence of genotypic resistance is presented for participants in the mITT Population who had Baseline and on-treatment genotypic resistance testing and who had successful sequencing.

  5. Number of Participants With Newly Emergent Phenotypic Resistance Using All On-treatment Isolates [ Time Frame: Week 24 ]
    Phenotypic resistance to a drug is defined as a fold change (i.e., ratio of the 50% inhibitory concentration (IC50) of the clinical isolate to the IC50 of the reference strain) which is greater than the cut-off for reduced susceptibility. Emergent phenotypic resistance to BMS-955176/GSK3532795 was defined as a Baseline fold change IC50<= 3 and an on-treatment fold change IC50>3. The number of participants with newly emergent phenotypic resistance is presented for participants in the mITT Population who had Baseline and on-treatment phenotypic resistance testing. The outcome was originally designed to be assessed up to 96 weeks of treatment, but it was analyzed up to Week 24 as the study was terminated early.

  6. Change From Baseline in Logarithm to the Base 10 (log10) HIV-1 RNA Over Time [ Time Frame: Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84 ]
    Blood samples were collected for analysis of HIV-1 RNA. Values obtained at Day 1 were considered as Baseline value. Change from Baseline was calculated as value at indicated time point minus Baseline value. Change from Baseline in plasma HIV-1 RNA (log10) is summarized over time for the mITT Population using observed values, which excluded participants without HIV-1 RNA result data in the assessment visit windows due to discontinuation and who discontinued on or after the date of site notification of study termination by the sponsor (10 October 2016). Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time point.

  7. Change From Baseline in Cluster of Differentiation (CD)4+ Thymus (T)-Cell Counts Over Time [ Time Frame: Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84 ]
    CD4+ T-cell counts was assessed using flow cytometry. Values obtained at Day 1 were considered as Baseline value. Change from Baseline was calculated as value at indicated time point minus Baseline value. Change from Baseline in CD4+T- cell counts is summarized over time for the mITT Population using observed values, which excluded participants without HIV-1 RNA result data in the assessment visit windows due to discontinuation and who discontinued on or after the date of site notification of study termination by the sponsor (10 October 2016). Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time point.

  8. Change From Baseline in the Percentage of CD4+ T-cells Over Time [ Time Frame: Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72 and 84 ]
    CD4+ T-cell counts overall was assessed using flow cytometry. Values obtained at Day 1 were considered as Baseline value. Change from Baseline was calculated as value at indicated time point minus Baseline value. Change from Baseline in percentage of CD4+T- cell counts is summarized over time for the mITT Population using observed values, which excluded participants without HIV-1 RNA result data in the assessment visit windows due to discontinuation and who discontinued on or after the date of site notification of study termination by the sponsor (10 October 2016). Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time point.

  9. Number of Participants With Serious Adverse Events (SAEs) and Adverse Events Leading to Discontinuation (AELD) [ Time Frame: Up to Week 96 ]
    Any untoward medical occurrence that at any dose: results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention were categorized as SAE. Number of participants with SAEs and AELDs is summarized.

  10. Number of Participants With at Least One Centers for Disease Control (CDC) Class C Events [ Time Frame: Up to Week 96 ]
    The occurrence of new AIDS defining events that is CDC class C events is presented.

  11. Maximum Observed Plasma Concentration (Cmax), Observed Pre-dose Plasma Concentration (C0) and Observed Plasma Concentration at the End of a Dosing Interval (Ctau) of BMS-955176/GSK3532795 [ Time Frame: Pre-dose (morning) and at 0.5, 1, 1.5, 2, 4, 4.5, 5, 6, 8, 12 (evening pre-dose) and 24 hours (morning pre-dose) at Week 2 (Days 12 to 16) ]
    Serial blood samples were collected at indicated time points for intensive pharmacokinetic (PK) assessment. The PK assessments were performed on evaluable PK Population, a sub-population which included all treated participants who had adequate PK profiles.

  12. Time of Maximum Observed Plasma Concentration (Tmax) of BMS-955176/GSK3532795 [ Time Frame: Pre-dose (morning) and 0.5, 1, 1.5, 2, 4, 4.5, 5, 6, 8, 12 (evening pre-dose) and 24 hours (morning pre-dose) at Week 2 (Days 12 to 16) ]
    Serial blood samples were collected at indicated time points for intensive PK assessment.

  13. Area Under the Concentration-time Curve in One Dosing Interval (AUC [Tau]) of BMS-955176/GSK3532795 [ Time Frame: Pre-dose (morning) and at 0.5, 1, 1.5, 2, 4, 4.5, 5, 6, 8, 12 (evening pre-dose) and 24 hours (morning pre-dose) at Week 2 (Days 12 to 16) ]
    Serial blood samples were collected at indicated time points for intensive PK assessment.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com.

Inclusion Criteria:

  • Men and non-pregnant women, at least 18 years of age
  • Antiretroviral treatment-naïve; defined as no current or previous exposure to > 1 week of an antiretroviral drug
  • Plasma HIV-1 RNA ≥ 1000 copies/mL
  • CD4 T-cell count > 200 cells/mm3

Exclusion Criteria:

  • Resistance or partial resistance to any study drug determined by tests at Screening
  • Current or historical genotypic and/or phenotypic drug resistance testing showing certain resistance mutations to EFV, TDF, FTC, Protease Inhibitors
  • Chronic hepatitis B virus (HBV)/ hepatitis C virus (HCV)
  • Blood tests that indicate normal liver function
  • Hemoglobin < 8.0 g/dL, platelets < 50,000 cells/mm3

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02415595


  Show 64 Study Locations
Sponsors and Collaborators
ViiV Healthcare
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials ViiV Healthcare

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT02415595     History of Changes
Other Study ID Numbers: 205891
2013-005487-26 ( EudraCT Number )
AI468-038 ( Other Identifier: Bristol-Myers Squibb )
First Posted: April 14, 2015    Key Record Dates
Results First Posted: September 19, 2018
Last Update Posted: September 19, 2018
Last Verified: August 2018

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Acquired Immunodeficiency Syndrome
HIV Infections
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Emtricitabine
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents